"When my Brother Fell, I Picked Up His Weapons": Collective Remembrance as Community Mobilization among Black Gay, Bisexual, and Queer Men.

The Counter Narrative Project (CNP) was founded to shift narratives and shatter stereotypes about Black gay, bisexual, and queer men to advance social justice. This paper describes three programs CNP implemented that were organized around collective memory as a strategy to respond to collective trauma experienced by this community.

Exploring the mental health of black men who have sex with men.

Current research indicates that black men who have sex with men (MSM) are disproportionately burdened by depressive distress and anxiety disorders as compared to their white gay and heterosexual counterparts. This study utilizes focus groups to qualitatively explore issues surrounding the mental health status of this population in an attempt to shed light on potential influencing and determinant factors. Twenty-two self-identified black, or multi-racial including black, MSM residing in Atlanta, Georgia participated in two focus groups--11 subjects each, respectively. Categories that emerged from data analysis include: knowledge/experiences, attitudes/beliefs, societal action/behavior, identity development, relationship functionality, and mental health status. Overarching themes for each category were delineated.

Repurposed drug screen identifies cardiac glycosides as inhibitors of TGF-ß-induced cancer-associated fibroblast differentiation.

The tumor microenvironment, primarily composed of myofibroblasts, directly influences the progression of solid tumors. Through secretion of growth factors, extracellular matrix deposition, and contractile mechanotransduction, myofibroblasts, or cancer-associated fibroblasts (CAFs), support angiogenesis and cancer cell invasion and metastasis. The differentiation of fibroblasts to CAFs is primarily induced by TGF-ß from cancer cells. To discover agents capable of blocking CAF differentiation, we developed a high content immunofluorescence-based assay to screen repurposed chemical libraries utilizing fibronectin expression as an initial CAF marker. Screening of the Prestwick chemical library and NIH Clinical Collection repurposed drug library, totaling over 1700 compounds, identified cardiac glycosides as particularly potent CAF blocking agents. Cardiac glycosides are traditionally used to regulate intracellular calcium by inhibiting the Na+/K+ ATPase to control cardiac contractility. Herein, we report that multiple cardiac glycoside compounds, including digoxin, are able to inhibit TGF-ß-induced fibronectin expression at low nanomolar concentrations without undesirable cell toxicity. We found this inhibition to hold true for multiple fibroblast cell lines. Using real-time qPCR, we determined that digoxin prevented induction of multiple CAF markers. Furthermore, we report that digoxin is able to prevent TGF-ß-induced fibroblast contraction of extracellular matrix, a major phenotypic consequence of CAF differentiation. Assessing the mechanism of inhibition, we found digoxin reduced SMAD promoter activity downstream of TGF-ß, and we provide data that the effect is through inhibition of its known target, the Na+/K+ ATPase. These findings support a critical role for calcium signaling during CAF differentiation and highlight a novel, repurposable modality for cancer therapy.

The Arf-like GTPase Arl8b is essential for three-dimensional invasive growth of prostate cancer in vitro and xenograft formation and growth in vivo.

Cancer is a multistep process that requires cells to respond appropriately to the tumor microenvironment, both in early proliferative stages and in later invasive disease. Arl8b is a lysosome localized Arf-like GTPase that controls the spatial distribution of lysosomes via recruitment of kinesin motors. Common features of the tumor microenvironment such as acidic extracellular pH and various growth factors stimulate lysosome trafficking to the cell periphery (anterograde), which is critical for tumor invasion by facilitating the release of lysosomal proteases to promote matrix remodeling. Herein we report for the first time that Arl8b regulates anterograde lysosome trafficking in response to hepatocyte growth factor, epidermal growth factor, and acidic extracellular pH. Depletion of Arl8b results in juxtanuclear lysosome aggregation, and this effect corresponds with both diminished invasive growth and proteolytic extracellular matrix degradation in a three-dimensional model of prostate cancer. Strikingly, we found that depletion of Arl8b abolishes the ability of prostate cancer cells to establish subcutaneous xenografts in mice. We present evidence that Arl8b facilitates lipid hydrolysis to maintain efficient metabolism for a proliferative capacity in low nutrient environments, suggesting a likely explanation for the complete inability of Arl8b-depleted tumor cells to grow in vivo. In conclusion, we have identified two mechanisms by which Arl8b regulates cancer progression: 1) through lysosome positioning and protease release leading to an invasive phenotype and 2) through control of lipid metabolism to support cellular proliferation. These novel roles highlight that Arl8b is a potential target for the development of novel anti-cancer therapeutics.

The polyphenols (-)-epigallocatechin-3-gallate and luteolin synergistically inhibit TGF-ß-induced myofibroblast phenotypes through RhoA and ERK inhibition.

The presence of reactive stroma, predominantly composed of myofibroblasts, is directly associated with and drives prostate cancer progression. We have previously shown that (-)-Epigallocatechin-3-gallate (EGCG), in the form of Polyphenon E, significantly decreases serum levels of HGF and VEGF in prostate cancer patients. Given that HGF and VEGF are secreted from surrounding tumor myofibroblasts, these observations suggested that EGCG may inhibit prostate cancer-associated myofibroblast differentiation. Herein, we demonstrate that micromolar combinations of EGCG and a second polyphenol, luteolin, synergistically inhibit TGF-ß-induced myofibroblast phenotypes in prostate fibroblast cell lines, as observed primarily by potentiation of fibronectin expression. Functionally, EGCG and luteolin inhibited TGF-ß-induced extracellular matrix contraction, an enhancer of tumor cell invasion. EGCG and luteolin inhibited downstream TGF-ß-induced signaling, including activation of ERK and AKT, respectively, but mechanistically, only ERK appeared to be necessary for TGF-ß-induced fibronectin expression. Furthermore, neither EGCG nor luteolin affected Smad signaling or nuclear translocation. Rho signaling was found to be necessary for TGF-ß-induced fibronectin expression and EGCG and luteolin each reduced RhoA activation. Finally, EGCG and luteolin were shown to reverse TGF-ß-induced fibronectin expression, implicating that these natural compounds may be useful not only in preventing but also in treating already activated myofibroblasts and the diseases they cause, including cancer. The ability of EGCG and luteolin to synergistically target myofibroblasts suggests that combined clinical use of these compounds could prevent or reverse cancer progression through targeting the tumor microenvironment, in addition to the tumor itself.

HeartBeat Connections: A Rural Community of Solution for Cardiovascular Health.

BACKGROUND: Cardiovascular disease (CVD) continues to be the leading cause of death among Americans. National guidelines emphasize early identification and control of CVD risk factors, but challenges remain in the primary care setting in terms of engaging patients and improving medical therapy adherence. The rapid growth of electronic health records (EHRs) provides a new way to proactively identify populations of high-risk patients and target them with prevention strategies. The HeartBeat Connections (HBC) program was developed as part of a population-based demonstration project aimed at reducing myocardial infarctions. METHODS: HBC uses EHR data to identify residents at high CVD risk in a rural community. Participants receive coaching from a registered dietitian or a registered nurse focused on lifestyle behavior changes and preventive medication initiation/titration. DISCUSSION: HBC provides patients with access to nonprescribing professionals on a more frequent basis than typical office visits, and it is focused specifically on helping patients improve lifestyle behaviors and medication adherence as they relate to the primary prevention of CVD. CONCLUSION: Innovative population health approaches that use EHR data to address common barriers to CVD prevention and engage communities in addressing population health needs are needed to help more patients prevent coronary events.

The Heart of New Ulm Project: using community-based cardiometabolic risk factor screenings in a rural population health improvement initiative.

Awareness of cardiovascular disease and diabetes risk factors can improve the health of individuals and populations. Community-based risk factor screening programs may be particularly useful for quantifying the burden of cardiometabolic risk in a given population, particularly in underserved areas. This study provided a description of a screening platform and how it has been used to monitor the cardiometabolic risk profile within the broader Heart of New Ulm Project, which is based in a rural Minnesota community. A cross-sectional, descriptive examination of baseline screening data indicated that 45% of the target population participated in the program over 8 months. Overall, 13% of the sample reported a personal history of diabetes or cardiovascular disease. Among the subset without active cardiometabolic disease, 35% were found to be at high risk for developing cardiovascular disease or type 2 diabetes over the next 8-10 years. A high prevalence of metabolic syndrome, high low-density lipoprotein cholesterol, obesity, and low fruit/vegetable consumption were of particular concern in this community. This article describes the use of screening results to inform the design of intervention programs that target these risk factors at both the community and individual levels. In addition, design considerations for future community-based cardiometabolic risk factor screening programs are discussed, with a focus on balancing program objectives related to health surveillance, research, and the delivery of preventive health care services.

Factors Influencing Depression and Anxiety among Black Sexual Minority Men.

The primary aim of this study was to examine the relationships between depression and anxiety, and ethnic and sexual identity development, and discrimination and harassment (DH) among Black sexual minority men. Additional aims were to determine whether an interaction effect existed between ethnic and sexual identity and whether coping skills level moderated these relationships. Using an observational cross-sectional design, 54 participants recruited through snowball sampling completed self-administered online surveys. Stepwise multiple regression analysis was used. Sixty-four percent of the variance in depression scores and 53% of the variance in anxiety scores were explained by DH and internalized homonegativity together. Thirty percent of the sample had scale scores indicating likelihood of depression and anxiety. Experience of DH and internalized homonegativity explained a large portion of the variability in depression and anxiety among Black sexual minority men. The study showed high prevalence of mental distress among this sample.